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WIREs Syst Biol Med
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Heart valve regeneration: the need for systems approaches

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Tissue‐engineered heart valves are promising alternatives to address the limitations of current valve replacements, particularly for growing children. Current heart valve tissue engineering strategies involve the selection of biomaterial scaffolds, cell types, and often in vitro culture conditions aimed at regenerating a valve for implantation and subsequent maturation in vivo. However, identifying optimal combinations of cell sources, biomaterials, and/or bioreactor conditions to produce functional, durable valve tissue remains a challenge. Despite some short‐term success in animal models, attempts to recapitulate aspects of the native heart valve environment based on ‘best guesses’ of a limited number of regulatory factors have not proven effective. Better outcomes for valve tissue regeneration will likely require a systems‐level understanding of the relationships between multiple interacting regulatory factors and their effects on cell function and tissue formation. Until recently, conventional culture methods have not allowed for multiple design parameters to be considered at once. Emerging microtechnologies are well suited to systematically probe multiple inputs, in combination, in high throughput and with great precision. When combined with statistical and network systems analyses, these microtechnologies have excellent potential to define multivariate signal–response relationships and reveal key regulatory pathways for robust functional tissue regeneration. WIREs Syst Biol Med 2016, 8:169–182. doi: 10.1002/wsbm.1329 This article is categorized under: Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models Developmental Biology > Stem Cell Biology and Regeneration
Heart valve anatomy and composition. (a) A native porcine aortic heart valve. (b) Movat's pentachrome staining of a porcine aortic heart valve depicting the three distinct layers. Scale bar is 200 µm. The Movat's pentachrome staining includes collagen in yellow, elastin and nuclei in purple, and proteoglycans in blue.
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Microtechnological advancements that can be utilized or adapted for combinatorial screening experiments. (a) Artificial niche microwell arrays printed with random or gradient patterns of fluorescein isothiocyanate labelled bovine serum albumin (FITC‐BSA) (green) or Rhodamine‐BSA (magenta). (Reprinted with permission from Ref . Copyright 2011 Macmillan Publishers Ltd: Nature Methods). (b) A schematic for the development and use of a 3D microarray platform for studying human mesenchymal stem cell osteogenic differentiation. (Reprinted with permission from Ref . Copyright 2014 Macmillan Publishers Ltd: Nature Methods). (c) A dynamic mechanical stretching device for culturing valvular interstitial cells. (Reproduced from Ref Macmillan Publishers Ltd: Scientific Reports. Copyright 2013 with permission of The Royal Society of Chemistry). (d) A deformable membrane stretching device that imparts flexural bending, akin to the aortic heart valve during diastole, to covalently bound polyethylene glycol norbornene (PEG‐NB) hydrogels. (Reprinted with permission from Ref . Copyright 2015 Elsevier: Acta Biomaterialia)
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A schematic depicting the strategies for heart valve tissue engineering. The scaffold material and geometry along with mechanical and chemical conditioning provide essential microenvironmental signals to cells, which enable the development of a tissue‐engineered heart valve.
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Developmental Biology > Stem Cell Biology and Regeneration
Biological Mechanisms > Cell Signaling
Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models

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